Project Abstract Approximately 350,000 people suffer out-of-hospital cardiac arrest (OHCA) each year, with an average survival rate with good neurological function of only 9.0%. In response to the clear public health imperative signaled by these statistics, the Institute of Medicine in 2015 called for studies on implementation of interventions for OHCA at the community, emergency medical services (EMS), and hospital levels. The lack of consistent use of effective interventions across the country is largely due to the lack of high quality evidence from randomized trials on how to implement these interventions at the systems (community) level. The proposed Regional Approaches to Cardiovascular Emergencies- Cardiac ARreSt (RACE-CARS) cluster-randomized trial has been designed to develop new systems-based high quality clinical trial evidence on how to improve outcomes for OHCA. The premise for RACE-CARS is based on prior observations showing substantial regional heterogeneity in care correlated with variations in outcomes. In 11 North Carolina counties, we observed improved rates of bystander CPR and first responder defibrillation, associated with a 37% increase in survival with good neurologic outcome over a 4-year period. RACE-CARS, a 7-year pragmatic, cluster randomized (1:1) trial of 50 counties in NC, will test whether implementation of a customized set of strategically targeted community-based interventions can improve survival to hospital discharge with good neurologic function in OHCA relative to control/standard care. Our intervention program will consist of 4 main elements: (1) optimized medical 911-dispatch performance with rapid recognition of cardiac arrest and dispatch of emergency response, (2) enhanced 911-dispatch telephone coaching of bystander CPR, (3) improved first responder performance with AED use, and (4) comprehensive public training of CPR and AED use. Quality of life and neurological functional status will be assessed at 6 and 12 months. RACE-CARS will leverage our statewide emergency care network, which has successfully collaborated on improving quality of emergency cardiovascular care over the past 14 years, and ongoing data collection of the majority of cardiac arrests in NC using the CARES registry. We will enroll ~20,000 patients with cardiac arrest over the study period, to give us >90% power to detect a 30% increase in bystander CPR, and 50% increase in bystander or first responder defibrillation, and > 85% power to detect a 33% increase in survival with good neurologic outcome. While all the intervention approaches have evidence for improved outcomes in prior observational studies, RACE CARS is unique in combining these efforts into a pragmatic randomized systems-based implementation trial that can be adjusted to the needs and abilities/resources of regions that vary according to population density, demographic and socioeconomic status. 1